BACKGROUND. Targeted therapeutic agents, including MEK and ERK kinase inhibitors, haves shown very limited efficacy against solid tumors with KRAS mutations. The identification of drug combinations that can synergistically kill KRAS mutant cancer cells could lead to new therapeutic modality. PURPOSE. In this project we aim to carry out a high-throughput drug combination screen to identify synergistic combinations that show strong selectivity in KRAS mutant cancer cells in vitro. We aim to validate hits from the screen and evaluate their translational potential. ACCOMPLISHMENT. We have completed the primary screen and have identified a candidate drug combination with synergistic cell killing effect in KRAS mutant cancer cell lines. We have identified the mechanism of drug synergy in vitro. We showed that a fraction of KRAS mutant pancreatic cancer cell lines are sensitive to this combination.